Common Endocrine Disorders. Gary L. Horowitz, MD Beth Israel Deaconess Medical Center Boston, MA

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1 Common Endocrine Disorders Gary L. Horowitz, MD Beth Israel Deaconess Medical Center Boston, MA

2 Objectives Describe the typical laboratory values for TSH and Free T4 in hypo- and hyperthyroidism Explain the cort stim test Explain why free testosterone is the exception to the rule regarding the importance of free hormone levels

3 Assays to be Covered Today PTH Cortisol Thyroid Function Tests Estradiol & Testosterone Pituitary

4 Themes Normal Appropriate Timing of Tests Stimulation/Suppression Tests Protein-Binding

5 Must be Something Wrong Here! Patient in OR for parathyroidectomy Pre-op Dx = Hyperparathyroidism Baseline PTH = 45 pg/ml, normal: (45 ng/l, normal 10-65) Could it be the correct patient? Can the value possibly be correct?

6 Two Dimensional Reference Intervals

7 Other PTH Issues N-terminal vs. C-terminal vs. Intact Rationale for Intra-Operative PTH Rapid T 1/2 (of Intact) Suppression of Remaining Glands don t close until you ve got the right one! re-operations 20% 5% chemistry trumps Anatomic Pathology??

8 Cortisol Chemical structure Diurnal variation CBG (Cortisol Binding Globulin) issues UFC (urinary free cortisol) for cortisol excess states

9 Steroid Hormone Pathways Burtis CA, Ashwood ER. Tietz Fundamentals of Clinical Chemistry. 4 th Edition

10 Diurnal Variation of Cortisol

11 Cortisol Deficiency Causes 1 0 : Addison s: vascular, infectious 2 0 : Pituitary (ACTH deficiency): tumor 3 0 : Hypothalamic (CRH deficiency): iatrogenic Important to distinguish 1 o vs 2 o /3 o

12 Cortisol Deficiency Laboratory Diagnosis Suspect with low peak (8am) cortisol Confirm with ACTH level not practical Burtis CA, Ashwood ER. Tietz Textbook of Clinical Chemistry. 3 rd Edition

13 Cortisol Deficiency Laboratory Diagnosis Suspect with low peak (8am) cortisol Confirm with ACTH level not practical Cosyntropin (ACTH analogue) Stimulation Test measure baseline + 30-minute cortisol normal response:» >7 ug/dl increase over baseline, or» absolute value >18 ug/dl (before or after dose) (497 nmol/l)

14 Cosyntropin (ACTH analogue) Stimulation Test Burtis CA, Ashwood ER. Tietz Textbook of Clinical Chemistry. 3 rd Edition

15 Cortisol Excess Semantics Cushing s Syndrome versus Disease Syndrome excess cortisol, from any cause Disease one specific cause: ACTH-secreting pituitary adenoma

16 Breakdown of Causes of Cushing s Syndrome

17 Cortisol Excess Laboratory Diagnosis Suspect with high nadir (4-8pm) cortisol many false positives Confirm with» Stress» Obesity, especially in women with PCO» Depression Dexamethasone Suppression Test Potent glucocorticoid (less is used) Little cross-reactivity with cortisol immunoassays vs Urinary Free Cortisol (UFC)

18 Rationale for UFC When serum cortisol exceeds CBG serum level increases gradually urine level increases abruptly free (unlike bound) cortisol is filtered Also, 24 o -urine has integrating power diurnal variation dilemma eliminated Increased Diagnostic Power of Urine Increasing Incremental Amount of Cortisol

19 Cortisol Excess Laboratory Diagnosis Suspect with high nadir (4-8pm) cortisol many false positives» Stress» Obesity, especially in women with PCO» Depression Confirm with Dexamethasone Suppression Test Potent glucocorticoid (less is used) Little cross-reactivity with cortisol immunoassays vs Urinary Free Cortisol (UFC) vs Serum Free Cortisol??? vs Midnight Salivary Cortisol???

20 Thyroid Hormones (and their precursors) Burtis CA, Ashwood ER. Tietz Fundamentals of Clinical Chemistry.4 th Edition

21 Common Thyroid Disorders Hypothyroidism Subclinical Hypothyroidism Hyperthyroidism Sick Euthyroid Syndrome

22 Thyroid Function Tests (TFTs) Useful TSH (concept of generation) FreeT4 (not all FreeT4 assays are good) Useless Total T4 T-uptake T3 Reverse T3

23 Thyroid Hormone Physiology Most T4 is deiodinated peripherally to T3 T4 serves as reservoir for active hormone, T3 Acute illness/stress causes T4 rt3

24 Thyroid Hormone Binding Issues 99.97% of T4 is protein-bound! 0.03% is free wide variations in binding protein concentrations wide variations in Total T4 (but not FreeT4) e.g., pregnancy

25 Paradigm for Thyroid Disease Check TSH: Should be high in hypothyroidism (>5.0 miu/l) Has always worked well Should be low in hyperthyroidism (<0.3 miu/l) Until recently (3 rd Gen TSH), has not worked well So, need to assess T4 (or FreeT4): should be high

26 Analytic Sensitivity How low can you measure reliably? (Is there a little bit there, or is it 0?) tumor markers & recurrence TSH, too Two major definitions ± 2 SD of 0-calibrator (or of negative sample) analytic sensitivity level at which inter-assay CV rises above 20% functional sensitivity

27 What Do Those TSH Generations Mean? Answer: Better Precision at Lower Concentrations 27

28 Historical Perspective Measure Total T4 (easy) Correct Total T4 for Binding Proteins Measure T-uptake (original assay= Resin T3-Uptake ) Or Measure TBG by immunoassay correct T4 by this amount Estimating the FreeT4 this way is: like counting the number of cows on a field by counting the number of feet and dividing by 4 James D. Faix, MD Why not just measure the FreeT4?

29 Free T4 Measurements Difficult to measure 0.03% of anything! Estimated Resin T3-Uptake (RIA) Automated T-Uptake Measured TBG Measured Equilibrium Dialysis (the gold standard) Automated Analogue Tests 1-step 2-step

30 (1 o ) Hypothyroidism [By Definition, Elevated TSH] Often, FreeT4 is low (as expected) Sometimes, FreeT4 is normal! subclinical hypothyroidism clinical significance: Should we wait until people are frankly hypothyroid? Should we screen asymptomatic people?» prevalence is high (women older than 40)» hypercholesterolemia, lack of energy, etc. Recent data: screening probably not indicated (but we do 350 TSHs/day on outpatients!)

31 (1 o ) Hyperthyroidism [By Definition, Low TSH] in true hyperthyroidism, TSH should be undetectable <0.05 (shades of normal PTH) sometimes, it s low but detectable (>0.05 miu/l) Sick Euthyroid Syndrome TSH is low, but detectable because FreeT4 is normal (not high) Solution: Measure FreeT4 (well) Other lessons: don t do TFTs on sick patients (unless thyroid is thought to be central issue)

32 Common Thyroid Disorders Laboratory Diagnosis Elevated TSH Check FreeT4 Low FT4 Hypothyroidism [TSH >10.0] Normal FT4 Subclinical Hypothyroidism [TSH ] Low TSH Check FreeT4 High FT4 Hyperthyroidism [TSH<0.05] Normal FT4 Sick Euthyroid Syndrome [TSH ] vs Subclinical Hyperthyroidism

33 A Few Slides on Androgens/Estrogens (Time Permitting)

34 Testosterone Terminology Testosterone Total = Free + SHBG-bound + Albumin-Associated In contrast to cortisol and T4, Free Testosterone is not the best indicator Rather, Bioavailable Testosterone =Total SHBG-bound = Albumin-Associated + Free ~ Albumin-Associated >> Free)

35 Testosterone Fractions (and misleading lab reports) 1488 ng/dl (51.6 nmol/l) 15 ng/dl ( 1% of total) 312 ng/dl (30% of total) Appears that Free T is 10% of total and 50% of bioavailable T In fact, it s just 1% of total and 5% of bioavailable T To extent that Free T is in equilibrium with bioavailable T, 35 Free T may be acceptable to use in place of bioavailable T

36 Proper Ordering of Free Testosterone Expert recommendations: For men: nmol/l Total T <100: No further testing needed <3.47 Total T : Free T or Bioavailable T Total T : Normal Total T >1000: No further testing needed >34.7 For women: Total T < 80: No further testing needed <2.78 Total T > 80: Free or Bioavailable T >

37 Free Testosterone Several methods in use: Analogue immunoassay Mass spectrometry Calculated from Total T, SHBG, and albumin: De Ronde W et al Clin Chem 2006;52: NB: Testosterone is exception to the rule: free hormone is not really the most important parameter rather, bioavailable (= Free T + Albumin-T = Total T SHBG-T) 37

38 Hirsutism in Women Two sources of androgens in women Ovaries: testosterone + DHEA-SO4 Adrenals: DHEA-SO4 Don t forget about DHEA-SO4!

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40 Hormones Associated with the Menstrual Cycle

41 Menopause: Laboratory Diagnosis? When ovaries stop functioning, Estradiol (E2) levels fall How low is undetectable? analytic sensitivity (again) FSH/LH levels rise Does low E2 + high FSH/LH = menopause? No! Menopause is a clinical diagnosis

42 Pituitary Hormones Posterior Oxytocin ADH Anterior ACTH Cortisol TSH T4 ( T3) FSH/LH Estradiol & Testosterone PRL GH macroprolactin: a big issue in PRL testing

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44 Self-Assessment Question 1 Which of the following represents typical hypothyroidism? A) High TSH, High Free T4 B) High TSH, Low Free T4 C) Low TSH, High Free T4 D) Low TSH, Low Free T4

45 Self-Assessment Question 2 Which of the following is a reasonable screening test for Cushing s syndrome? A) A low serum cortisol at night B) A low serum cortisol in the morning C) A high serum cortisol at night D) A high serum cortisol in the morning

46 Self-Assessment Question 3 When screening men for hypogonadism, which one of the following results is ambiguous and requires an additional chemistry test (e.g., SHBG)? A) A total serum testosterone 90 ng/dl (3.12 nmol/l) B) A total serum testosterone of 250 ng/dl (8.68 nmol/l) C) A total serum testosterone of 500 ng/dl (17.4 nmol/l) D) A total serum testosterone of 800 ng/dl (27.8 nmol/l)

47 Answers 1 (B) High TSH, Low Free T4 2 (C) A high serum cortisol at night 3 (B) A total serum testosterone of 250 ng/dl (8.68 nmol/l)